Titratable dosage transdermal delivery system

ABSTRACT

The present invention relates to a titratable dosage transdermal delivery system for systemic delivery of a therapeutic agent or drug. The system comprises a plurality of patch units that are connected along one or more borders. The plurality of patch units are divisible into units along the one or more borders having one or more lines of separation. Each patch unit is surrounded by a border. The therapeutic patch has at least a backing layer and a therapeutic agent comprising layer. The dosage of therapeutic agent delivered to a patient is proportional to the number of patch unit applied per treatment. The system enables systemic administration of a titratable dosage of therapeutic agent, adjustable by the patient under the direction of a physician, through the skin or mucosa. Moreover, the invention relates to a method of making the titratable dosage transdermal delivery system. Furthermore, the invention relates to a method of providing a titratable amount of therapeutic agent to a patient using the transdermal delivery system of the invention.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of pending prior U.S.patent application Ser. No. 10/690,384 filed Oct. 20, 2003, which is acontinuation of U.S. patent application Ser. No. 09/714,604, filed Nov.16, 2000, now U.S. Pat. No. 6,682,757, both of which are incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates generally to a transdermal delivery systemwhich is applied onto the skin or mucosa of a host, for systemicdelivery of a therapeutic agent. More particularly, the invention isdirected to a titratable dosage transdermal delivery system thatcomprises a plurality of patch units connected along one or moreborders. The plurality of patch units are divisible into respectiveunits along the one or more borders having one or more lines ofseparation. The dosage provided by the transdermal delivery system isproportional to the number of units applied by the user as determined bya physician. Each patch unit comprises at least a backing layer and adrug layer formulated with at least one therapeutic agent. Thetransdermal delivery system enables administration of a titratabledosage of therapeutic agent on a solid support to the skin or mucosa ofa host. Furthermore, the invention is directed to a method of making thetransdermal delivery system. Still further, the invention is directed toa method of providing a titratable amount of therapeutic agent to a hostusing the transdermal delivery system of the invention.

BACKGROUND OF THE INVENTION

One approach to sustained delivery of a therapeutic agent is the use oftransdermal delivery system such as transdermal patches. Generally,transdermal patches contain a therapeutic agent and an adhesive whichallows the transdermal device to adhere to the skin of a patient,allowing for the passage of the active agent from the device through theskin of the patient. Various advantages of using transdermal patchesinclude constant rate of delivery of therapeutic agent, longer durationof action (the ability of the patch to adhere to the skin for 1, 3, 7days or longer), non-invasive application, improved patient compliance,and the supply of therapeutic agent may be interrupted at any time bytearing off the system. The importance of this means of administrationresides in the fact that therapeutic agent can be delivered to thebloodstream without traversing the gastro-intestinal tract and avoidinga “first pass” through the hepatic system prior to reaching the targetsite. This would avoid any gastrointestinal incompatibility with thepharmaceuticals and unwanted destruction of the pharmaceuticals bymetabolism in the gastrointestinal tract. Once the therapeutic agent haspenetrated the skin layer, it is absorbed into the blood stream where itcan exert a desired pharmacotherapeutic effect. These benefits may beobtained without requiring a professional to administer the therapeuticagent. Transdermal absorption minimizes inter- and intra-patientvariations regarding such incompatibilities and metabolisms. Bytransdermal absorption, it is deemed possible to provide more constantpharmaceutical concentration in the body and to realize a greaterpharmaceutical efficiency. It is possible, by proper transdermalabsorption, to provide effective dosing of therapeutic agent.

Current pharmaceutical practice provides for transdermal system ortransdermal patch that delivers therapeutics at fixed dosages. The rateof delivery of therapeutic agent from the patch to the skin or mucosa ofa host, known as the flux rate, is constant and predetermined by theindividual patch that is prescribed. The economics of manufacturing andgovernment approval limit the availability of patches with differentdosages. Presently, a pharmacist needs to stock multiple patches eachcontaining various dosages of therapeutic agents. For example, apharmacist needs to stock five different types of transdermal patch,each having dosage strengths such as 25, 50, 75, 100, 150 units per time(micrograms/hour). When a doctor prescribed a certain patch having acertain dosage strength to a patient, the patient purchases enoughsupply of transdermal patches having the fixed dosage of therapeuticagent. If the prescribed amount is too strong, the patient will have topurchase another supply of transdermal patches having a reduced dosageof therapeutic agent. If the prescribed amount is too weak, the patientwill have to purchase another supply of transdermal patches having anincreased dosage of therapeutic agent. In this current practice, patchesthat do not provide the optimum dosage for the patient are being wasted.

Thus, there remains a long felt, yet currently unmet need to provide atransdermal delivery system that can deliver titratable dosage oftherapeutic agent. This titratable dosage transdermal delivery systemhas the advantage of minimizing wastage of transdermal patches that donot provide optimal dosage level of therapeutic agent. There is also aneed for a transdermal system which allows fine control of dosage oftherapeutic agent to be delivered to a patent. The transdermal deliverysystem of the present invention solves the problem by providingadjustable dosage of therapeutic agent from a single transdermaldelivery system. This invention reduces the number of different types oftransdermal patch having various dosage strengths that need to bestocked by a pharmacist. For example, the pharmacist mentioned abovewould only need to stock two types of transdermal delivery system of thepresent invention. One type has a dosage of 25 units per patch and thesecond type has a dosage of 75 units per patch unit. From these twotypes of patches, it is possible to deliver various dosage strengthssuch as 25, 50, 75, 100, 150 units. For example, in order to achieve astrength of 50 units, 2 patches of the 25 unit dosage per patch unit maybe used. To achieve a strength of 100 units, 4 patches of the same typeof patch may be used. To achieve a strength of 150 units, 2 patches ofthe 75 unit dosage per patch unit may be used. Instead of stocking fivedifferent kinds of patches containing different dosages, only twodifferent kinds of patches need to be stocked.

SUMMARY OF THE INVENTION

The present invention is based upon the observation of the inventor thatan optimal dosage of therapeutic agent may be delivered to the skin ormucosa of a host, by means of a titratable dosage transdermal deliverysystem. The present system addresses three shortcomings of the currenttechnology. First, with the advent of transdermal patch,self-administration by a patient is generally involved. Patientcompliance with application instructions takes on great importance. Thepresent system provides an easy method of adjusting the dosage oftherapeutic agent by the patient through the use of the system of theinvention by following simple instructions from the physician. Second,the present system reduces the number of therapeutic patches withdifferent dosages that need to be stocked by a pharmacist. Third, thepresent system reduces wastage of transdermal patches that havesuboptimal dosage of therapeutic agent.

It is an object of this invention to provide a titratable dosagetransdermal delivery system for the systemic delivery of one or moretherapeutic agents to the skin or mucosa of a host.

The system comprises a plurality of patch units connected along one ormore borders. Each patch unit comprises: a backing layer having a topsurface and a bottom surface; a drug layer disposed on the top surfaceof the backing layer; and a means for adhering the patch unit onto theskin or mucosa of a host layer, where each patch unit is defined by oneor more lines of separation on the border.

In one embodiment, the system comprises a plurality of patch unitsconnected along one or more borders. Each patch unit comprises: (a) abacking layer having a top surface and a bottom surface; (b) a druglayer with matrix layer disposed on the top surface of the backinglayer; and (c) an adhesive layer disposed on the drug layer with matrixlayer, wherein each patch unit is defined by one or more lines ofseparation on the border.

In one embodiment, the system comprises a plurality of patch unitsconnected along one or more borders. Each patch unit comprises: (a) abacking layer having a top surface and a bottom surface; (b) a druglayer with matrix layer disposed on the top surface of the backinglayer; (c) an adhesive layer disposed on the drug layer with matrixlayer; and (d) a cover layer disposed on the adhesive layer, whereineach patch unit is defined by one or more lines of separation on theborder.

In another embodiment, the transdermal delivery system comprises aplurality of patch units connected along one or more borders. Each patchunit comprises: a backing layer having a top surface and a bottomsurface; a drug and adhesive layer disposed on the top surface of thebacking layer; and a cover layer disposed on the adhesive layer, whereineach patch unit is defined by one or more lines of separation on theborder.

Moreover, it is an object of the present invention to provide atransdermal delivery system which comprises a plurality of patch unitsconnected along one or more borders. Each patch unit comprises: abacking layer having a top surface and a bottom surface; a drug andadhesive layer disposed on the top surface of the backing layer; arelease limiting layer disposed on the drug and adhesive layer; a seconddrug and adhesive layer disposed on the release limiting layer; and acover layer disposed on the release limiting layer, wherein each patchunit is defined by one or more lines of separation on the border.

In addition, it is an object of the present invention to provide amethod of making the transdermal delivery system which delivers atitratable dosage of drugs to a patient. The method comprises forming abacking layer with top and bottom surfaces, which backing layer isdivided into more than one unit at one or more lines of separation. Adrug-in-matrix layer is disposed on the top surface of each unit of thebacking layer, leaving a border on all sides of the backing layer. Anadhesive layer is disposed on the drug-in-matrix layer and the border ofthe backing layer. A cover layer is then disposed on top of the adhesivelayer.

Still further, in one embodiment, the method comprises forming aplurality of reservoir compartments within an enclosure defined by theraised wall directly on a backing layer. Each reservoir compartment issurrounded by a border having a surface. One or more lines of separationare formed on the border dividing the plurality of the reservoircompartments into separate units. A drug layer is disposed into each ofthe reservoir compartments. An adhesive layer is then disposed on top ofthe drug layer and on the surface of the border. A cover layer is thendisposed on the adhesive layer which covers the surface of the borderand the adhesive layer.

Furthermore, it is an object of the present invention to provide amethod of making the transdermal delivery system which delivers atitratable dosage of drugs to a patient. The method comprises forming abacking layer with top and bottom surfaces, which backing layer isdivided into more than one units at one or more lines of separation. Adrug-in-adhesive layer is disposed on the top surface of each unit ofthe backing layer, leaving a border on all sides of the backing layer. Acover layer is disposed on top of the adhesive layer.

Moreover, in one embodiment, the method comprises the steps of forming abacking layer with top and bottom surfaces, which backing layer isdivided into more than one units at one or more lines of separation. Adrug-in-adhesive layer is disposed on the top surface of each unit ofthe backing layer, leaving a border on all sides of the hacking layer. Asemi-permeable membrane is disposed on the backing film so as to holdthe drug-in-adhesive within the border. A second drug-in-adhesive layeris disposed on the semi-permeable membrane. The border is covered withan adhesive. A cover layer is disposed on the drug-in-adhesive layer.

Finally, it is an object of the present invention to provide a method ofdelivering a therapeutic agent through the skin or mucosa of a patient.The method comprises providing a transdermal delivery system; separatinga prescribed number of units of patches from the transdermal deliverysystem along at least one line of separation; and removing the coverlayer exposing the adhesive layer and applying it on the skin or mucosa.

BRIEF DESCRIPTION OF THE DRAWINGS

The various advantages and novel features of this invention will be moreapparent from a reading of the Detailed Description of the PresentInvention in conjunction with the accompanying drawings in which likereference numerals refer to like parts.

FIG. 1 illustrates a schematic diagram showing an embodiment of thetransdermal delivery system of the invention.

FIG. 2 illustrates a schematic diagram showing an embodiment of thetransdermal delivery system of the invention.

FIG. 3 a illustrates a schematic diagram showing a cross-section of amatrix type transdermal delivery system of the invention.

FIG. 3 b illustrates a schematic diagram showing a cross-section of areservoir type transdermal delivery system of the invention.

FIG. 3 c illustrates a schematic diagram showing a cross-section of amonolithic drug-in-adhesive type transdermal delivery system of theinvention.

FIG. 3 d illustrates a schematic diagram showing a cross-section of amultilaminate drug-in-adhesive type transdermal delivery system of theinvention.

DETAILED DESCRIPTION OF THE INVENTION Transdermal Delivery System of theInvention

In general, this invention is directed to a divisible transdermaldelivery system which can deliver a titratable dosage of therapeuticagent to the skin or mucosa of a patient. The system of the presentinvention comprises a plurality of patch units joined together along oneor more borders. In other words, the system comprises divisible units oftherapeutic patch, thus delivering a controlled amount of therapeuticagent proportional to the number of patch units as desired. Asillustrated in FIG. 1, the titratable transdermal delivery system 10comprises a plurality of units. In this embodiment, there are four (4)units 20 in the system 10 arranged in 2 columns with 2 rows (i.e. 2×2format). Each unit 20 comprises four borders 30 surrounding atherapeutic delivery zone 40. The plurality of therapeutic patches aredivisible along the border. The border may be perforated to form a lineof separation which facilitates division of the therapeutic patches intoone or more units comprising one or more doses of therapeutic agent. Inthis embodiment, each unit 20 has two lines of separation 50.

In another embodiment as illustrated in FIG. 2, the titratabletransdermal delivery system 10 comprises a plurality of therapeuticpatch units arranged in a single row. Here, there are five (5) units 20in the system 10. Each unit 20 comprises four borders 30 surrounding atherapeutic delivery zone 40. Similar to the embodiment in FIG. 1, theplurality of therapeutic patches are divisible along the border. In thisembodiment, the two (2) units 20 at the ends of the transdermal deliverysystem 10 have one line of separation 50 whereas the three (3) units atthe middle of the transdermal delivery system have two lines ofseparation.

A patch suitable for use with the invention should contain at least: (1)a backing layer and (2) a therapeutic agent comprising layer. Each patchunit is surrounded by a border which is free of therapeutic agents. Thepatch may comprise an adhesive means for securing to the surface of theskin or mucosa. In a preferred embodiment, a cover layer is also presentto protect the therapeutic agent comprising layer. In another preferredembodiment, the cover layer comprises a hermetic peelable seal which maybe formed by heat sealing or an adhesive. In another preferredembodiment, the cover layer has a notch which provides for easyseparation of the cover layer from the patch.

Preferred patches that are suitable for use in this invention include,for example, (1) the matrix type patch; (2) the reservoir type patch;(3) the monolithic drug-in-adhesive type patch; and (4) themulti-laminate drug-in-adhesive type patch (Ghosh, T. K.; Pfister, W.R.; Yum, S. I. Transdermal and Topical Drug Delivery Systems, InterpharmPress, Inc. p. 249-297). These patches are well known in the art. Otherpatches may be useful for the present invention as determined by one ofskill in the art.

For practice of the invention, the matrix type patches are the mostpreferred.

Matrix Type Transdermal System

FIG. 3 a illustrates an embodiment of the system of the invention whichutilizes a matrix patch. The matrix patch comprises a backing layer 60which comprises two opposing surfaces. One of the surface is in contactwith a drug with matrix layer 70, which is a matrix layer containing atherapeutic agent, and an adhesive layer 80. The drug with matrix layer70 does not cover the entire area of the patch unit but are confined atthe drug delivery zone 40 as shown in FIGS. 1 and 2, leaving a border 30surrounding the drug delivery zone 40. A line of separation 50 dividesthe borders 30 of adjacent patch units 20. The line of separationfacilitates the division of the system into separate units. The line ofseparation may be formed by perforations or weaknesses created in thebacking layer.

In a preferred embodiment, a release liner (not shown) is disposed onthe adhesive layer 80 or the drug with matrix layer 70. In some cases,it may be necessary to include an impermeable layer (not shown) on thesurface of the backing layer 60 that is in contact with the drug withmatrix layer 70 to minimize drug migration into the backing film (e.g.,U.S. Pat. No. 4,336,243). The matrix containing the therapeutic agent isheld against the skin by the adhesive layer 80. Adhesives may also bepresent on the surface of the borders 30 to provide further adhesion forthe patch to the skin.

The backing layer may be formed of woven or braided fibers or wires,membranes, porous or fibrous scaffolds made of a polymer. The polymer(s)useful for forming the therapeutic patch should be ones that arebiocompatible and avoid irritation to the skin or mucosa. The backinglayer can be made of a pharmaceutically acceptable material which isimpermeable to the therapeutic agent used. The backing layer preferablyserves as a protective cover for the therapeutic agent and may alsoprovide a support function. Examples of materials suitable for makingthe backing layer are synthetic polymers like films of high and lowdensity polyethylene, polypropylene, polyvinylchloride, polyurethane,polyesters such as poly(ethylene phthalate), metal foils, metal foillaminates of suitable polymer films, textile fabrics. Other examples forbacking materials are from natural materials like cotton, wool, etc.Preferably, the materials used for the backing layer are laminates ofsuch polymer films with a metal foil such as aluminum foil. Onepreferred type of backing material is nonwoven urethane material, suchas described in, for example, U.S. Pat. No. 5,230,701 to Meyer et al.More preferably the backing films are occlusive and comprised of apolyolefin oil. Occlusive backing films, such as synthetic polyesters,result in hydration of the outer layers of the stratum corneum whilenon-occlusive backings allow the area to breath (i.e., promote watervapor transmission from the skin surface). The backing layer can be anyappropriate thickness which will provide the desired protective andsupport functions. A suitable thickness will be from about 10 to about200 microns. Desirable materials and thickness will be apparent to theskilled artisan.

Generally, the matrix layer is formed from biologically acceptablepolymers capable of forming thin walls or coatings through whichpharmaceuticals can pass at a controlled rate. Examples of suitablematrix materials include but are not limited to lipophilic polymers,such as polydimethylsiloxane, and hydrophilic polymers likepolyvinylpyrrolidone, polyvinyl alcohol, hydrogels based on gelatin, orpolyvinylpyrrolidone/polyethylene oxide mixtures. A non-limiting list ofexemplary materials for inclusion in the polymer matrix includespolyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethylacrylate copolymers, ethylenevinyl acetate copolymers,silicones, rubber, rubber-like synthetic homo-, co- or block polymers,polyacrylic esters and the copolymers thereof, polyurethanes,polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinylchloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel),polyvinylidene chloride, poly(ethylene terephthalate), ethylene-vinylalcohol copolymer, ethylene-vinyloxyethanol copolymer, siliconesincluding silicone copolymers such as polysiloxane-polymethacrylatecopolymers, cellulose polymers (e.g., ethyl cellulose, and celluloseesters), polycarbonates, polytetrafluoroethylene and mixtures thereof.

Preferred materials for inclusion in the matrix layer can be anysilicone elastomers of the general polydimethylsiloxane structures,e.g., silicone polymers. Preferred are cross-linked silicone polymersthat are pharmaceutically acceptable. Other preferred materials forinclusion in the polymer matrix layer include: silicone polymers thatare cross-linkable copolymers having dimethyl and/or dimethylvinylsiloxane units which can be crosslinked using a suitable peroxidecatalyst. Also preferred are those polymers consisting of blockcopolymers based on styrene and 1,3-dienes (particularly linearstyrene-isoprene-block copolymers of styrene-butadiene-blockcopolymers), polyisobutylenes, polymers based on acrylate and/ormethacrylate.

The polymer matrix layer may optionally include a pharmaceuticallyacceptable crosslinking agent. Suitable crosslinking agents include,e.g., tetrapropoxy silane.

An adhesive layer may be used to affix the transdermal patch to the skinof the patient for a desired period of administration, e.g., about 5 toabout 8 days. If the adhesive layer of the transdermal patch fails toprovide adhesion for the desired period of time, it is possible tomaintain contact between the transdermal patch with the skin by, forinstance, affixing the transdermal patch to the skin of the patient withan adhesive tape, e.g., surgical tape. It is not critical for purposesof the present invention whether adhesion of the transdermal patch tothe skin of the patient is achieved solely by the adhesive layer of thetransdermal patch or in connection with a peripheral adhesive source,such as surgical tape, provided that the transdermal patch is adhered tothe patient's skin for the requisite administration period.

The adhesive layer is preferably an active ingredient permeable adhesivelayer that joins the device to the skin or mucosa of the host. It isalso preferably dermatologically acceptable. Each active ingredientpermeable adhesive layer is preferably a pressure-sensitive adhesive.Any of the well-known, dermatologically acceptable, pressure-sensitiveadhesives which permit drug migration therethrough can be used in thepresent invention.

Some suitable permeable adhesives include acrylic or methacrylic resinssuch as polymers of alcohol esters of acrylic or methacrylic acids andalcohols such as n-butanol, isopentanol, 2-methylbutanol,1-methylbutanol, 1-methylpentanol, 2-methylpentanol, 3-methylpentanol,2-ethyl-butanol, isooctanol, n-decanol, or n-dodecanol, alone orcopolymerized with ethylenically unsaturated monomers such as acrylicacid, methacrylic acid, acrylamide, methacrylamides, N-alkoxymethylacrylamides, N-alkoxymethyl methacrylamides, N-t-butylacrylamide,itaconic acid, vinyl acetate, N-branched alkyl maleamic acids whereinthe alkyl group has 10-24 carbon atoms, glycol diacrylates, or mixturesof these monomers; polyurethane elastomers; vinyl polymers such aspolyvinyl alcohol, polyvinyl ethers, polyvinyl pyrrolidone, andpolyvinyl acetate; urea formaldehyde resins; phenol formaldehyde resins,resorcinol formaldehyde resins; cellulose derivatives such asethylcellulose, methylcellulose, nitrocellulose, cellulose acetatebutyrate and carboxymethylcellulose; and natural gums such as guar,acacia, pectina, starch, destria, gelatin, casein, etc. Other suitablepressure-sensitive adhesives include polyisobutylene pressure-sensitiveadhesives, rubber pressure-sensitive adhesives and siliconepressure-sensitive adhesives. The adhesives may also be compounded withtackifiers and stabilizers as is well-known in the art. Any of the wellknown dermatologically acceptable hypoallergenic pressure-sensitiveadhesives can be used in practicing this invention. Exemplary adhesivesinclude acrylic or methacrylic resins such as polymers of esters ofacrylic or methacrylic acid with alcohols such as n-butanol, n-pentanol,isopentanol, 2-methyl butanol, 1-methyl butanol, 1-methyl penanol,2-methyl penanol, 3-methyl pentanol, 2-ethyl butanol, isooctanol,n-decanol, or n-dodecanol, alone or copolymerized with ethylenicallyunsaturated monomers such as acrylic acid, methacrylic acid, acrylamide,methacrylamide, N-alkoxymethyl acrylamides, N-alkoxymethylmethacrylamides, N-tert.butylacrylamide, itaconic acid, vinylacetate,N-branched alkyl maleamic acids wherein the alkyl group has 10 to 24carbon atoms, glycol diacrylates, or mixtures of these; natural orsynthetic rubbers such as styrenebutadiene, butylether, neoprene,polyisobutylene, polybutadiene, and polyisoprene; polyvinylacetate;ureaformaldehyde resins; phenolformaldehyde resins; resorcinolformaldehyde resins, cellulose derivatives such as ethyl cellulose,methyl cellulose, nitrocellulose, cellulose acetatebutyrate, andcarboxymethyl cellulose; and natural gums such as guar, acacia, pectins,starch, dextrin, albumin, gelatin, casein, etc. The adhesives may becompounded with tackifiers and stabilizers as is well known in the art.

Adhesives that are preferred for their active agent permeability includeacrylic copolymer adhesives such as Avery Chemical Company's AS-351 HSX,preferably at a coating weight of between 25 and 35 g/m.sup.2. Thispressure-sensitive adhesive is a cross-linkable polymer which provides apermanently tacky film having a total solids content of about 52%,Brookfield viscosity (LVT/Spindle No. 4/12 RPM@25.degree. C.) of fromabout 15,000 to 25,000 cps. at a weight per gallon of about 7.4 lbs. Itcan also be diluted with hexane or toluene to a desired solids and/orviscosity range, particularly for use in conventional coating equipment.

In preferred embodiments, the transdermal patch includes a removableprotective cover layer. The protective cover layer is removed prior toapplication, and consists of the materials used for the backing layerdescribed above provided that they are rendered removable, for example,by a silicone treatment. Other removable protective cover layers, forexample, are polyletra-fluoroethylene, treated paper, allophane,polyvinyl chloride, and the like. Generally, the removable protectivelayer is in contact with the adhesive layer and provides a convenientmeans of maintaining the integrity of the adhesive layer until thedesired time of application.

In another preferred embodiment, the transdermal delivery systemcomprises a plurality of therapeutic patches which are stored in aresealable pouch.

Reservoir Type Transdermal System

FIG. 3 b illustrates an embodiment of the system of the presentinvention which uses a reservoir type patch. The reservoir type patchdesign is characterized by a backing layer 60 and a reservoircompartment 90 containing a drug layer 75 preferably, in the form of asolution or suspension, that is separated from the skin by asemipermeable membrane (not shown) (e.g., U.S. Pat. No. 4,615,699). Thereservoir compartment 90 is a continuation of backing layer 60. Thebacking layer 60 is molded and formed having sidewalls 35 that definesthe protected volume of the reservoir compartment 90. The amount of drugthat may be placed within the reservoir compartment 90 is defined by thedimensions of the reservoir compartment 90 and the height of thesidewalls 35. The backing layer 60 has an upper surface 65, a side wall35, defining a drug delivery zone 40 as shown in FIGS. 1 and 2, and areservoir compartment 90 extending throughout the entire drug deliveryzone 40. An adhesive layer 80 is disposed on top of the drug layer 75and on the surface of the backing layer 65 which extends around thereservoir's boundaries, forming the border 30, so as to provide a sealwith the skin and hold the reservoir adjacent to the skin or mucosawhere a desirable number of unit patches of the transdermal system maybe applied. At the border, a line of separation 50 extends throughoutthe raised walls 100 that are formed by the backing layer 60.

In one embodiment, the drug delivery zone 40 is rectangular.Alternatively, the drug delivery zone 40 may be a variety of shapes,such as, but not limited to, oval, circular, elliptical, triangular,rectangular, hexagonal. In a preferred embodiment, the drug deliveryzone 40 has the same shape and therefore concentric to a patch unit ofthe transdermal system.

Other pharmaceutically acceptable compounds which may be included in thereservoir or matrix include: solvents, for example alcohols such asisopropanol; permeation enhancing agents such as those described infra;and viscosity agents, such as cellulose derivatives, natural orsynthetic gums, such as guar gum, and the like.

Certain preferred transdermal delivery systems also include a softeningagent in the reservoir or matrix. Suitable softening agents includehigher alcohols such as dodecanol, undecanol, octanol, esters ofcarboxylic acids, wherein the alcohol component may also be apolyethoxylated alcohol, diesters of dicarboxylic acids, such asdi-n-butyladiapate, and triglycerides particularly medium-chaintriglycerides of the caprylic/capric acids or coconut oil, have provedto be particularly suitable. Further examples of suitable softeners aremultivalent alcohols, for example, levulinic acid, cocprylic acidsglycerol and 1,2-propanediol which can also be etherified bypolyethylene glycols.

Monolithic Drug-in-Adhesive Transdermal System

FIG. 3 c illustrates an embodiment of the system of the presentinvention that uses a monolithic drug-in-adhesive patch. The monolithicdrug-in-adhesive patch design is characterized by the inclusion of thetherapeutic agent formulation in the skin contacting adhesive layerforming the drug-in-adhesive layer 100, a backing layer 60 andpreferably, a release liner (not shown). The adhesive releases thetherapeutic agent and also adheres the patch to the skin. Thedrug-in-adhesive system does not require a separate adhesive layer andthus the patch thickness is minimized (e.g., U.S. Pat. No. 4,751,087).Therefore, drug-in-adhesive type patches are thin and comfortable. Asillustrated in FIGS. 1 and 2, each unit of the transdermal systemcomprises one or more borders made of the backing layer surrounding adrug delivery zone 40. The drug-in-adhesive layer 100 does not cover theentire area of the unit of the patch but are confined at the drugdelivery zone 40 as shown in FIGS. 1 and 2, leaving a border 30surrounding the drug delivery zone 40. The border 30 is covered with anadhesive to further secure the unit of the therapeutic patch onto theskin. As in any patch designs, the plurality of therapeutic patches aredivisible along the border. The border may be perforated to form a lineof separation 50 which facilitates division of the therapeutic patchesinto one or more patch units comprising one or more doses of therapeuticagent or drug respectively.

Multilaminate Drug-in-Adhesive Transdermal System

FIG. 3 d illustrates an embodiment of the system of the presentinvention that utilizes a multi-laminate drug-in-adhesive patch. Themulti-laminate drug-in-adhesive patch design further incorporatesadditional semi-permeable membrane 200 between two or more distinctdrug-in-adhesive layers 100 under a single backing layer 60 (Peterson,T. A. and Dreyer, S. J. Proceed. Intern. Symp. Control. Rel. Bioact.Mater. 21: 477-478). Each layer of the drug-in-adhesive layer 100 or thesemi-permeable membrane 200 does not cover the entire area of the patchunit but are confined at the drug delivery zone as shown in FIGS. 1 and2, leaving a border 30 surrounding the drug delivery zone. The edges 150of each of the semi-permeable membrane 200 are secured to the backingfilm 60 so as to hold the drug-in-adhesive layer in place. The border 30is covered with an adhesive to further secure the therapeutic patch unitonto the skin. As in any patch designs, the plurality of therapeuticpatches are divisible along the border. The border may be perforated toform a line of separation 50 which facilitates division of thetherapeutic patches into one or more units comprising one or more dosesof therapeutic agent or drug respectively.

In one embodiment, a release limiting layer may be used with any patchdesigns especially the reservoir or multi-laminate patch, including thinnon-porous ethylene vinyl acetate films or thin microporous films ofpolyethylene employed in microlaminate solid state reservoir patches.Suitable release limiting layer include but are not limited toocclusive, opaque, or clear polyester films with a thin coating ofpressure sensitive release liner (e.g., silicone-fluorsilicone, andperfluorcarbon based polymers). The release limiting layer materials ofthis invention, which may or may not be rate controlling as desired, areknown in the art. The release limiting layers are commercially availableand can be made by a multitude of different methods, as described in R.E. Kesting, Synthetic Polymer Membranes, McGraw Hill, Chapters 4 and 5,1971; J. D. Ferry, Ultrafiltration Membranes, Chemical Review, Vol. 18,Page 373, 1934. In order to obtain the most advantageous results, thematerials should be formed into structures with the desired morphologyin accordance with methods known to those skilled in the art to achievethe desired release rate of drug. Additionally, the material must havethe appropriate chemical resistance to the drug used and be non-toxicwhen used as an element of the patch of the invention. Materials usefulin forming a rate controlling limiting layer used in this inventioninclude, but are not limited to the following: Polycarbonates, i.e.,linear polyesters of carbonic acids in which carbonate groups recur inthe polymer chain, by phosgenation of a dihydroxy aromatic such asbisphenol A. Such material are sold under the trade designation Lexan bythe General Electric Company. Polyvinylchlorides; one such material issold under the trade designation Geon 121 by B. G. Goodrich ChemicalCompany. Polyamides such as polyhexamethylene adipamide and other suchpolyamides popularly known as “nylon”. Modacrylic copolymers, such asthat sold under the trade designation DYNEL are formed ofpolyvinylchloride (60 percent) and acrylonitrile (40 percent),styrene-acrylic acid copolymers, and the like. Polysulfones such asthose of the type characterized by diphenylene sulfone groups in thelinear chain thereof are useful. Such materials are available from UnionCarbide Corporation under the trade designation P-1700. Halogenatedpolymers such as polyvinylidene fluoride sold under the tradedesignation Kynar by Pennsalt Chemical Corporation, polyvinylfluoridesold under the trade name Tedlar by E. I. DuPont de Nemours & Co., andthe polyfluorohalocarbon sold under the trade name Aclar by AlliedChemical Corporation. Polychlorethers such as that sold under the tradename Penton by Hercules Incorporated, and other such thermoplasticpolyethers. Acetal polymers such as the polyformaldehyde sold under thetrade name Delrin by E. I. DuPont de Nemours & Co., and the like.Acrylic resins such as polyacrylonitrile polymethyl methacrylate, polyn-butyl methacrylate and the like. Other polymers such as polyurethanes,polyimides, polybenzimidazoles, polyvinyl acetate, aromatic andaliphatic, polyethers, cellulose esters, e.g., cellulose triacetate;cellulose; collodion (cellulose nitrate with 11% nitrogen); epoxyresins; olefins, e.g., polyethylene polypropylene; porous rubber; crosslinked polyethylene oxide; cross-linked polyvinylpyrrolidone;cross-linked polyvinyl alcohol; polyelectrolyte structures formed of twoionically associated polymers of the type as set forth in U.S. Pat. Nos.3,549,016 and 3,546,141; derivatives of polystyrene such as polysodiumstyrenesulfonate and polyvinylbenzyltrimethyl-ammonium chloride;polyhydroxyethylmethacrylate; polyisobutylvinyl ether, and the like, mayalso be utilized. A large number of copolymers which can be formed byreacting various proportions of monomers from the aforesaid said list ofpolymers are also useful for preparing rate controlling limiting layerutilized in the invention.

The rate controlling release limiting layer can have varying thicknessdepending upon the nature of the membrane, its porosity and the numberof membranes used in combination. Typically, a thickness of from 20 to200 microns is employed.

Applicable Therapeutic Agents

The applicable therapeutic agents which can be placed on the transdermalpatch can be any therapeutic substances or drugs. The therapeutic agentcan be of various physical states, e.g., molecular distribution, crystalforms or cluster forms. A therapeutic agent may be encapsulated byliposomes. Liposome comprising therapeutic agent useful in the presentinvention may be prepared in a number of ways known in the art. Forexample, microencapsulation techniques for the preparation ofmicrocapsules having a wall or membrane of polymeric material aredescribed in literature such as “Microencapsulation and Related DrugProcesses” by P. D. Deasy, Marcel Dekker Inc. New York (1984).

In practicing this invention one can employ any systemically active drugwhich may be absorbed by the body surface to which the transdermal patchis applied, consistent with their known dosages and uses. Of course, theamount of drug necessary to obtain the desired therapeutic effect willvary depending on the particular drug used. Suitable systemic drugs foradministration by the claimed system include those useful in treatingemesis and nausea as described in U.S. Pat. No. 4,031,894, e.g.,preferably, scopolamine. Other suitable systemic drugs are disclosed inU.S. Pat. No. 3,996,934 and include, without limitation, anti-microbialagents such as penicillin, tetracycline, oxytetracycline,chlortetracycline, chloramphenicol, and sulfonamides; potent narcoticsand analgesics such as fentanyl and etorphine; and local anaestheticssuch as buprenorphine, penzocaine, morphine and morphine derivatives,lidocaine, prilocaine, mepivacaine or non-steroidalantirheumatics/anti-inflammatories such as indometnacin, diclofenac oretopenamate; sedatives such as pentabarbital sodium, phenobarbital,secobarbital sodium, codeine, (a-bromoisovaleryl)urea, carbromal, andsodium phenobarbital, psychis energizers such a 3-(2-aminopropyl)indoleacetate and 3-(2-aminobutyl)indole acetate; tranquilizers such asreserpine, chlorpromazine hydrochloride, and thiopropazatehydrochloride; hormones such as adrenocorticosteroids, for example6-α-methylprednisolone; androgenic steroids, for example,methyltestosterone, and fluoxymesterone; estrogenic steroids, forexample estrone, 17-β-estradiol and ethinyl estradiol; progesterone, andnorethindrone; and thyroxine; antipyretics such as aspirin,salicylamide, and sodium salicylate; morphine and other narcoticanalgesics; anti-diabetics, e.g., insulin; cardiovascular agents, e.g.nitroglycerin, and cardiac glycosides such as digitoxin, digoxin,ouabain; anti-spasmodics such as atropine, methscopolamine bromide,methscopolamine bromide with phenobarbital; anti-malarials such as the4-aminoquinolines, 9-amino-quinolines, and pyrimethamine; andnutritional agents such as vitamins, essential amino acids, andessential fats.

Additionally, in practicing this invention one can employ a wide varietyof topically active drugs consistent with their known dosages and uses.Suitable drugs include, without limitation: antiperspirants, e.g.,aluminum chloride; deodorants, e.g., hexachloraphene, methylbenzethoniumchloride; astringents, e.g., tannic acid; irritants, e.g., methylsalicylate, camphor, cantharid; keratolytics, e.g., benzoic acid,salicylic acid, resorcinol, iodochlorhydroxyquin; antifungal agents,such as tolnaftate, griseofulvin, nystatin and amphotericin;anti-inflammatory agents, such as corticosteroids, e.g., hydrocortisone,hydrocortisone acetate, prednisolone, methylprednisolone, triamoinoloneacetonide, fludrocortisone, flurandrenolone, flumethasone, dexamethasonesodium phosphate, bethamethasone, dexamethasone sodium phosphate,bethamethasone valerate, fluocinolone acetonide; fluorometholone; andpramoxine HCl; anti-neoplastic agents, e.g. methotrexate, andantibacterial agents, such a bacitracin, neomycin, erythromycin,tetracycline HCl, chlortetracycline HCl, chloramphenicol,oxytetracycline, polymyxin B, nitrofuraxone,mafenide(alpha.-amino-p-toluenesulfonamide), hexachlorophene,benzalkonium chloride, cetalkonium chloride, methylbenzethoniumchloride, and neomycin sulfate.

It will be appreciated, with regard to the aforesaid list of drugs thecharacterization of the drug as either “systemically or topically”active is for classification purposes, a given drug can be bothsystemically and topically active depending upon its manner of use.

Drugs employed to assist in treating problems associated with cardiacdilation may be a suitable therapeutic agent for use in the presentinvention. For example, digoxin angiotensin-converting enzyme, ACEinhibitors, such as captopril and enalopril, may be used.

Other suitable drugs include the coronary vasodilators described in U.S.Pat. No. 3,742,951 such as compounds having nitrate moiety. Somesuitable coronary vasodilators include organic and inorganic nitratessuch as amyl nitrate, nitroglycerin (glyceryl trinitrate), sodiumnitrate, erythrityl tetranitrate, pentaerythritol tetranitrate,isosorbide dinitrate, mannitol hexanitrate, trolnitrate phosphate(triethanolamine biphosphate), and the like. Nitroglycerine is apreferred coronary vasodilator. Also suitable are the beta adrenegicblocking drugs such as propanolol.

When practicing the invention, antifungal agents such as ciclopirox,chloroxylenol, triacetin, sulconazole, nystatin, undecylenic acid,tolnaftate, miconizole, clotrimazole, oxiconazole, griseofulvin,econazole, ketoconozole, and amphotericin B may be incorporated.Antibiotic agents such as mupirocin, erythromycin, clindamycin,gentamicin, polymyxin, bacitracin, silver sulfadiazine, and the like mayalso be used. Antiseptic agents such as iodine, Povidine-iodine,benzalkonium chloride, benzoic acid, chlorhexidine, nitrofurazone,benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol,resorcinol, and cetylpyridinium chloride likewise could be incorporatedinto the topical drug formulation or the patch. Furthermore,anti-inflammatories such as hydrocortisone, prednisone, triamcilolone,betamethasone, dexamethasone, and the like may be incorporated.

In addition to the aforementioned drugs, simple pharmacologicallyacceptable derivatives of the drugs, such as ethers, esters, amides,acetals, salts, etc., or formulations of these drugs, having the desiredpolymeric permeability or transport or transport properties can beprepared and used in practicing the invention. Drugs mentioned above canbe used along or in combination with others and each other.

The above drugs and other drugs can be present in the therapeutic patchof the invention alone or in combination form with pharmaceuticalcarriers. The pharmaceutical carriers acceptable for the purpose of thisinvention are the known in the art carriers that do not adversely affectthe drug, the host, or the material comprising the transdermal deliverysystem. Suitable pharmaceutical carriers include sterile water; saline,dextrose; dextrose in water or saline, condensation products of castoroil and ethylene oxide combining about 30 to 35 moles of ethylene oxideper mole of castor oil; liquid glyceryl triester of a lower molecularweight fatty acid; lower alkanols, oils such as corn oil, peanut oil,sesame oil and the like, hydrocarbons such as mineral oils andsilicones, with emulsifiers such as mono- or di-glyceride of a fattyacid, or a phosphatide, e.g., lecithin, and the like; glycols;polyalkylene glycols; aqueous media in the presence of a suspendingagent, for example, sodium carboxymethylcellulose; sodium alginate;polyvinyl pyrrolidone; and the like, alone, or with suitable dispersingagents such as lecithin; polyoxyethylene stearate; and the like. Thecarrier may also contain adjuvants such as preserving, stabilizing,wetting, emulsifying agents, and the like.

A great number of systemically active drugs have been found to besuitable for administration via the transdermal route. Certainpharmaceuticals are absorbed to a degree through the skin. This isreferred to as transdermal pharmaceutical absorption. It has been foundthat the transdermal absorption rates of certain pharmaceuticals can beincreased by use of absorption promoting compounds (also referred to asskin permeation enhances) with the pharmaceutical to be absorbed.

Penetration enhancers can be included in the drug formulation or patch,to optimize delivery into and through the skin. Ghosh, T. K. et al.1993, Pharm. Tech. 17(3):72-98; Ghosh, T. K. et al. 1993, Pharm. Tech.17(4): 62-89; Ghosh, T. K. et al., 1993, Pharm. Tech. 17(5):68-76.Permeation enhancing agents are compounds which promote penetrationand/or absorption of the therapeutic agent into the blood stream of thepatient. The penetration enhancer should be pharmacologically inert,non-toxic, and non-allergenic, have rapid and reversible onset ofaction, and be compatible with the drug formulation (Pfister et al.,1990, Pharm. Tech. 14(9):132-140, incorporated herein by reference).Penetration enhancers suitable for the purpose of the invention do notadversely affect the host, the drug, or alter or adversely affect thematerials forming the transdermal delivery system. The penetrationenhances can be used alone or they can be admixed with acceptablecarriers and the like.

Useful penetration enhancers include but are not limited to ethylalcohol, isopropyl alcohol, or octolyphenylpolyethylene glycol. Morepreferred penetration enhancers include oleic acid, polyethylene glycol400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g.,isopropyl myristate, methyl laurate, glycerol monooleate, and propyleneglycol monooleate); N-methyl pyrrolidone; monovalent, saturated andunsaturated aliphatic cycloaliphatic and aromatic alcohols having 4 to12 carbon atoms, such as hexanol, cyclohexane and the like; aliphaticcycloaliphatic and aromatic hydrocarbons having from 5 to 12 carbonatoms such as hexane, cyclohexane, isopropylbenzene and the like;cycloaliphatic and aromatic aldehydes and ketones having from 4 to 10carbon atoms such as cyclohexanone; acetamide; N,N-di(lower)alkylacetamides such as N,N-diethyl acetamide, N,N-dimethyl acetamide,N-(2-hydroxyethyl)acetamide, and the like; and other transporting agentssuch as aliphatic, cycloaliphatic and aromatic esters;N,N-di(lower)alkyl sulfoxides; essential oils; halogenated or nitratedaliphatic, cycloaliphatic and aromatic hydrocarbons; salicylate;polyalkylene glycol silicates; surfactants; mixtures thereof; and thelike.

Alternatively, permeation of a therapeutic agent may be enhanced byremoving hair from the application site by, e.g. clipping, shaving oruse of a depilatory agent. Another permeation enhancer is heat. It isthought that heat enhancement can be induced by, among other things,using a radiating heat form, such as an infrared lamp, onto theapplication site after application of the transdermal patch.

Various methods may be used to place therapeutic agents or drugs ontothe patch. For example, the therapeutic agent may be placed onto thepatch by absorption, adsorption, chemical bond, and covalent bond.

For drug-in-matrix type patches, the therapeutic agent is dissolved orsuspended in a polymer matrix film through which the active agentdiffuses to the skin as disclosed in U.S. Pat. Nos. 4,839,174,4,908,213, and 4,943,435.

The therapeutic agents or drugs suitable for use in this invention maybe present in the reservoir, matrix, or microcapsules as explainedsupra. A carrier may be used together with the therapeutic agent whenplaced on the patch. The carrier material will typically be one of twotypes. One type bioerodes rather uniformly over time, so that thebioerosion of the carrier is also the primary mechanism for releasingthe drug from a patch. The second type is a material which essentiallyremains intact during a substantial portion of the release period of thedrug. The mechanism of release of the drug is by diffusion or othermechanism which does not require the carrier to be concurrentlybioeroded. Many carrier materials may be suitable for variousembodiments of the system of the present invention. These carriermaterials may be natural products, such as keratin, triglycerides, fattyacids, lipids, latexes, as well as derivatives, salts of cellulosederivatives, alkaline or alkaline earth salts of cellulose acetatephthalate, ammonium salts of hydroxypropyl methyl cellulose phthalate,polysaccharide, synthetic polymers, such as, polyglycolic acid andderivatives of polyethylene glycol, polycaprolactone, polylactic acid,and copolymers thereof; materials such as starch, fatty alcohols,alginate polymers, albumin, calcium caseinate, calcium polypectate orgellan gum.

Adhesives for use with the drug-in-adhesive type patch are well known inthe art and selection is readily accomplished by an ordinarypractitioner. Three basic types commonly used are polyisobutylenes,silicones, and acrylics. Adhesives useful in the present invention canfunction under a wide range of conditions, such as, high and lowhumidity, bathing, sweating etc. Preferably the adhesive is acomposition based on natural or synthetic rubber, polyacrylate,polyvinylacetate, polybutylacrylate, polymethylacrylate,polydimethylsiloxane, and hydrogels (e.g., high molecular weightpolyvinylpyrrolidone and oligomeric polyethylene oxide). The mostpreferred is polyacrylate.

Therapeutic agents or drugs may also be glued onto the patch by means ofa number of known synthetic, naturally-occurring or modifiednaturally-occurring substances which exhibit tackiness. The adhesiveshould be compatible with the material forming the carrier, as well asthe drug. A variety of adhesives are suitable for the present invention,both for adhering a patch on the skin or mucosa, and for retainingtherapeutic agent or drugs onto the patch. One adhesive is a hydrogelcomposed of gelatin and poly(L-glutamic acid) (PLGA). The hydrogel isformed by chemically cross linking gelatin and poly(L-glutamic acid).Another adhesive is fibrin glue. Suitable fibrin glue includesfibrinogen, thrombin, calcium chloride and factor VIII. Another familyof adhesives is cyanoacrylates. Preferred cyanoacrylates includebutyl-2-cyanoacrylate (Histoacryl), ethyl-2-cyanoacrylate, andoctyl-2-cyanoacrylate. Gelatin-resorcinol formaldehyde-glutaraldehyde isanother suitable adhesive. Others include carboxymethyl andhydroxypropyl methyl cellulose, and other cellulose derivatives;tragacanth, caraya, locust bean and other synthetic and natural gumssuch as algin, chitosan, starches, pectin, and naturally-occurringresins. In addition, many polymers having suitable adhesive propertiescan also be utilized, including without limitation: polyurethanes havingamino groups, di- and tri-functional diols; polyvinyl acetates;polyamides; polyvinyl alcohols; polyvinyl pyrrolidone, polyacrylic acid;polystyrene; polylactides; polylactones; block co-polymers includingpolyesters, polyamides, and polyurethanes; and combinations and mixturesthereof.

In another embodiment, the therapeutic agent is applied onto the patchas a coating or layer. More than one coating of different therapeuticagents may be applied to the patch so that more than one therapeuticagent and/or carrier may be incorporated onto the patch. The placementof the different layers may be determined by the diffusion or elutionrates of the therapeutic agent involved as well as the desired rate ofdelivering the therapeutic agent to the body tissue.

Selection of the appropriate dosage for transdermal delivery oftherapeutic agent is an important consideration. The amount of activeagent to be incorporated onto the patch to obtain the desiredtherapeutic effect will vary depending upon the desired dosage, thepermeability of the rate controlling materials of the patch which areemployed to the particular agent to be used, and the length of time thepatch is to remain on the skin or body mucosa. Since this invention isdesigned to provide titratable dosage of drug. The dosage provided bythe transdermal delivery system is proportional to the number of patchunit applied. The lower limit for dosages is determined by the fact thatsufficient amounts of the drug must remain in each patch unit tomaintain the minimum possible dosage. The dosages and dosing frequencywill be determined by a trained medical professional. The concentrationor loading of the therapeutic agent onto the therapeutic patch may bevaried according to the therapeutic effects desired. Also, the loading,in terms of the ratio of therapeutic agent to carrier in the patch willdepend upon the type of therapeutic agent and carrier used and the rateat which the therapeutic agent on the patch is released to the bodytissue. Generally, the patch may contain 0.1-90% by weight or preferably10-45% by weight of the therapeutic agent. Most preferably, 25-40% byweight of the therapeutic agent should be incorporated in the patch.

Concentrations of the drugs in the transdermal delivery system arevirtually unlimited since delivery rate is controlled in various typesof patches by a release limiting layer and an adhesive layer. However,the concentration must be at least great enough so that the drug willleave the vehicle once the protective cover layer is removed. Oneadvantage of the present invention is that should the amount ofdrug/unit area/unit time be insufficient to render an appropriate doseof the drug, additional units of the transdermal patch of the presentinvention may be employed. However, it is more advantageous to utilizeconcentrations of drug sufficiently high so that patch size is keptdown. Most advantageous are systems capable of delivering the drug in atherapeutically useful degree in an area reasonably related to theapplication site in view of medical, aesthetic, and patient convenienceconsiderations. These limitations are well known to product designers inthe art.

Method of Making the Transdermal Delivery System

The present invention also relates to methods of making the transdermaldelivery system. The method of the present invention generally involvesforming a backing layer with a top surface and a bottom surface. Thebacking layer is divided into more than one unit at one or more lines ofseparation. A drug layer is disposed on the top surface of each unit ofthe backing layer, leaving a border on all sides of each of the unit ofthe backing layer. An adhesive means is used to attach the transdermaldelivery system onto the skin or mucosa of the patient.

In one embodiment, the method further comprises disposing an adhesivelayer on the drug layer and the border of the backing layer. A coverlayer is then disposed on top of the adhesive layer. In one embodiment,the method of the present invention involves forming a backing layerwith a top surface and a bottom surface. The backing layer is dividedinto more than one unit at one or more lines of separation. Adrug-in-matrix layer is then disposed on the top surface of each unit ofthe backing layer, leaving a border on all sides of the backing layer.An adhesive layer is then disposed on the drug-in-matrix layer and theborder of the backing layer. Finally, a cover layer is disposed on topof the adhesive layer.

The lines of separation formed distinct patch units on the backinglayer. They also define each unit of the transdermal delivery system.The backing layer is made of materials as described supra. The backinglayer has one or more lines of separation. A plurality of lines ofseparation are preferably parallel and/or perpendicular to each other.The lines of separation are also preferably spaced at regular intervalsalong the length and/or width of the backing. Preferably, the lines ofseparation are about 1 cm to 6 cm apart. The lines of separation may bein various forms as long as they allow for relatively clean separationof a desired number of units of the transdermal delivery system by theuser as directed by a physician. The lines of separation may also be aweakness of the backing or a printed line of division so that a patientmay tear along or use scissors to cut along the line. A preferred lineof separation is a line of perforations. The weakness of the backing maybe a thinning of the backing that is molded or formed in the backing. Insome instances, it may be desirable to combine a line of weakness withperforations to ensure clean separation of the transdermal deliverysystem into a desired number of units for optimal dosage application.Other useful methods of constructing the lines of separation aredisclosed in U.S. Pat. No. 5,496,605. It is important that the lines ofseparation allow easy division of the transdermal delivery system intodesired number of units per application. Although the transdermaldelivery system have been described as a transdermal delivery systemhaving one or more lines of separation, those skilled in the art willunderstand that, alternatively, the present invention can also becharacterized as a plurality of units of transdermal delivery patchesconnected to each other along the same line or lines of separation.Regardless of the characterization, the present invention provides atransdermal delivery system for and method of delivering therapeuticagent or drug of varying dosages using a single transdermal deliverysystem.

A drug-in-matrix layer is formed by dissolving or suspending atherapeutic agent in a polymer matrix through which the active agentdiffuses to the skin. Methods of forming a drug-in-matrix layer aredisclosed in U.S. Pat. Nos. 4,839,174, 4,840,796, 4,908,213, and4,943,435. When a drug-in-matrix layer is disposed on the top surface ofeach unit of the backing layer, the drug-in-matrix layer is notcoextensive with the entire unit of the backing layer. A border is lefton all sides so that the backing layer is not entirely covered by thedrug-in-matrix layer. This is to prevent the drug from seeping throughthe lines of separation. Various methods may be used to place a drug onthe transdermal delivery system as discussed infra. An adhesive layer isthen disposed on the drug-in-matrix layer, the adhesive layer alsocovers the border of the backing layer. The border is preferably uniformin width and can range from about 0 (zero) cm to about 2.0 cm. A coverlayer is disposed on the adhesive layer so that each patch unit of thetransdermal delivery system is protected separately. A notch is formedon the cover layer so as to facilitate separation of the cover layerfrom the adhesive layer when the transdermal patch is ready for use.

The present invention further provides a method of making the system ofthe present invention which involves forming a plurality of reservoircompartments within an enclosure defined by the raised wall directly ona backing layer. Each reservoir compartment is surrounded by a borderhaving a surface. The plurality of the reservoirs are divided by one ormore lines of separation on the border. A drug layer is disposed ontoeach unit of the reservoir compartment. An adhesive layer is thendisposed on top of the drug layer and on the surface of the border. Acover layer is then disposed on the adhesive layer.

In this method of making a transdermal delivery system of the presentinvention, a plurality of reservoir compartments are formed on a backinglayer. As mentioned earlier, each patch unit is surrounded by a border.The sidewalls of the reservoir compartment may be formed on the backinglayer by raising the surrounding border or making a depression withinthe border. The height of the raised wall is determined by the quantityof therapeutic agent that is to be deposited in the reservoircompartment. However, it should be less than 5 mm so that it iscomfortable for use by the patient. Each reservoir compartment issurrounded by a border. A line of separation is present on the borderwhich allows the reservoir compartments to be separated into units.

The present invention also provides a method of making the system of thepresent invention which involves forming a backing layer with a topsurface and a bottom surface. The backing layer is divided into morethan one unit at one or more lines of separation. A drug-in-adhesivelayer is disposed on the top surface of each unit of the backing layer,leaving a border on all sides of the backing layer. Then, a cover layeris disposed on top of the adhesive layer.

In this method of making a transdermal delivery system of the invention,the drug-in-adhesive layer is formed by mixing one or more drugs with anadhesive and dispose the composition on the top surface of each unit onthe backing layer. A cover layer is disposed on the drug-in-adhesivelayer so that each unit of the transdermal delivery system is protectedseparately.

The present invention further provides a method of making the system ofthe present invention which involves forming a backing layer with a topsurface and a bottom surface. The backing layer is divided into morethan one unit at one or more lines of separation. A drug-in-adhesivelayer is disposed on the top surface of each unit of the backing layer,leaving a border on all sides of the backing layer. A semi-permeablemembrane is disposed on the drug-in-adhesive layer. The semi-permeablemembrane is secured to the backing film so as to hold thedrug-in-adhesive within the border. A second drug-in-adhesive layer isthen disposed on the semi-permeable membrane. The border is then coveredwith an adhesive. Finally, a cover layer is disposed on top of each unitpatch.

In this method of making a transdermal delivery system of the invention,the composition that is used to make a drug-in-adhesive layer is formedby mixing one or more drugs with an adhesive and dispose the compositionon the top surface of each unit on the backing layer within the border.

Method of Use for the Invention

The method of the present invention can be used to deliver therapeuticagents or drugs systemically through the skin or mucosa of a patient.

The method comprises the steps of providing a transdermal deliverysystem of the invention. The user then separates the prescribed numberof patch units from the transdermal delivery system along at least oneline of separation along the border. The cover layer is then removed,exposing the adhesive layer and applying the prescribed number of thetransdermal delivery patch units on the skin or mucosa. Alternatively,the user may remove the cover layer for a prescribed number of patchunits from the transdermal delivery system and then separates theprescribed number of patch units from the transdermal delivery system.Under the direction of a physician, the user may increase or decreasethe number of patch units used per application. In a preferredembodiment, the number of patch units used per application may be one,two, three, four or five.

The rate of transdermal delivery from the therapeutic patch is afunction of skin permeability, and skin permeability has been shown tovary between anatomical sites depending on the thickness of the stratumcorneum. For example, the permeability, in general, increases in orderfrom planter foot arch, lateral ankle, palm, ventral forearm, dorsalforearm, back, chest, thigh, abdomen, scalp, axilla, forehead, andscrotum (Wester, R. C. and Maibach, H. I. (1989) Regional variation inPercutaneous Absorption: In Percutaneous Absorption, Mechanism,Methodology, Drug Delivery, 2^(nd) ed., Eds. R. L. Bronaugh and H. I.Maibach, Marcel Dekker, Inc., New York, pp. 111-119).

The transdermal delivery system of the invention may be applied directlyto any area of the patient's skin, with the lower back, chest, upperarm, and buttocks being the areas of choice. In like manner, the patchcan be applied to the mucosa of the mouth, for example, by applicationto the palate or the buccal mucosa, to obtain absorption of the drug bythe oral mucosa. Similarly, where desired and accessible, the patch canbe applied to other mucosa membranes.

In a preferred embodiment, the transdermal delivery system comprising aplurality of therapeutic patch units is stored in a resealable pouch.For each application, the transdermal delivery system is removed fromthe pouch and a prescribed number of patch units are removed from thepouch and applied on the skin or mucosa of a patient. The remainingpatch units are placed in the resealable pouch.

In a preferred embodiment, the sustained delivery of the therapeuticagent will be for an extended period, longer than about three days andpreferably, at least about one week. For treatment of cancer or otherchronic conditions, it is preferred that the drug be delivered over aperiod up to about one month.

Whereas the invention has been shown and described in connection withspecific embodiments hereof, many modifications, substitutions andadditions may be made which are within the intended broad scope of theappended claims. Thus, it should be understood that the presentinvention encompasses the use of other methods and titratable dosagetransdermal delivery systems for systemic delivery of adjustable dose oftherapeutic agent to a patient.

Various references are cited herein, the disclosure of which areincorporated by reference in their entireties.

What is claimed:
 1. A method of delivering a drug through a patient'sskin comprising: (a) providing a transdermal delivery system thatcomprises a plurality of patch units, wherein each patch unit comprisesa backing layer having one or more borders, a drug layer comprising adrug disposed on the backing layer, and an adhesive layer, wherein thedrug is a narcotic analgesic, a local anesthetic, a sedative, atranquilizer, or a combination thereof, and wherein at least a portionof the adhesive layer is disposed on the borders of the backing layer;the plurality of patch units are connected to each other along one ormore borders of the patch units; and each patch unit is defined by oneor more lines of separation along the borders of the patch units; (b)separating at least one patch unit from the transdermal delivery systemalong at least one line of separation; and (c) applying at least onepatch unit such that the drug layer makes contact with the skin.
 2. Themethod of claim 1 wherein the patch units are applied on the skin of theplanter foot arch, lateral ankle, palm, upper arm, ventral forearm,dorsal forearm, back, chest, thigh, abdomen, scalp, axilla, forehead,lower back, chest, buttocks or scrotum.
 3. The method of claim 1 whereina portion of the adhesive layer is disposed on the drug layer; and acover layer is disposed on the adhesive layer.
 4. The method of claim 1wherein the drug is fentanyl, etorphine, buprenorphine, penzocaine,morphine, morphine derivative, lidocaine, prilocaine, mepivacaine,pentabarbital sodium, phenobarbital, secobarbital sodium, codeine,(a-bromoisovaleryl)urea, carbromal, sodium phenobarbital, or acombination thereof.
 5. The method of claim 3 wherein said transdermaldelivery system further comprises a release limiting layer disposed onthe drug layer.
 6. The method of claim 1 wherein the drug isencapsulated by microcapsules.
 7. The method of claim 1 wherein the druglayer comprises about 0.1-90% by weight of the drug.
 8. The method ofclaim 1 wherein the drug layer comprises about 10-45% by weight of thedrug.
 9. The method of claim 1 wherein the drug layer comprises about25-40% by weight of the drug.
 10. The method of claim 1 wherein the druglayer further comprises a softening agent, wherein the softening agentis dodecanol, undecanol, octoanol, esters of carboxylic acids, or acombination thereof.
 11. The method of claim 1 wherein the drug layerfurther comprises a permeation enhancing agent.
 12. The method of claim3 wherein the cover layer comprises a notch so as to facilitateseparation of the cover layer from the adhesive layer.
 13. The method ofclaim 1 wherein the transdermal delivery system is stored in aresealable pouch.
 14. The method of claim 1 wherein the lines ofseparation are parallel and/or perpendicular to each other.
 15. Themethod of claim 1 wherein the lines of separation are lines ofperforations.
 16. The method of claim 1 wherein the lines of separationare spaced at regular intervals.
 17. The method of claim 1 wherein thelines of separation are about 1 cm to 6 cm apart.
 18. The method ofclaim 1 wherein 2 to 5 patch units are connected in series in thetransdermal delivery system.
 19. The method of claim 1 wherein 4 patchunits are arranged in 2 rows and 2 columns in the transdermal deliverysystem.
 20. The method of claim 1 wherein the drug layer is a reservoirlayer.
 21. The method of claim 1 wherein the drug layer is adrug-in-matrix layer.
 22. The method of claim 1 wherein the drug layeris a drug-in-adhesive layer.
 23. The method of claim 1 wherein two tofive patch units are applied on the skin.
 24. A method of delivering adrug through a patient's skin comprising: (a) providing a transdermaldelivery system that comprises a plurality of patch units, wherein eachpatch unit comprises a backing layer having one or more borders, a druglayer comprising fentanyl disposed on the backing layer, and an adhesivelayer, wherein at least a portion of the adhesive layer is disposed onthe borders of the backing layer; the plurality of patch units areconnected to each other along one or more borders of the patch units;and each patch unit is defined by one or more lines of separation alongthe borders of the patch units; (b) separating at least one patch unitfrom the transdermal delivery system along at least one line ofseparation; and (c) applying at least one patch unit such that the druglayer makes contact with the skin.
 25. A method of delivering a drugthrough a patient's skin comprising: (a) providing a transdermaldelivery system that comprises a plurality of patch units, wherein eachpatch unit comprises a backing layer having one or more borders, a druglayer comprising buprenorphine disposed on the backing layer, and anadhesive layer, wherein at least a portion of the adhesive layer isdisposed on the borders of the backing layer; the plurality of patchunits are connected to each other along one or more borders of the patchunits; and each patch unit is defined by one or more lines of separationalong the borders of the patch units; (b) separating at least one patchunit from the transdermal delivery system along at least one line ofseparation; and (c) applying at least one patch unit such that the druglayer makes contact with the skin.
 26. A method of delivering a narcoticanalgesic through a patient's skin comprising: (a) providing atransdermal delivery system that comprises a plurality of patch units,wherein each patch unit comprises a backing layer having one or moreborders, a drug layer comprising a narcotic analgesic disposed on thebacking layer, and an adhesive layer, wherein at least a portion of theadhesive layer is disposed on the borders of the backing layer; theplurality of patch units are connected to each other along one or moreborders of the patch units; and each patch unit is defined by one ormore lines of separation along the borders of the patch units; (b)separating at least one patch unit from the transdermal delivery systemalong at least one line of separation; and (c) applying at least onepatch unit such that the drug layer makes contact with the skin.
 27. Themethod of claim 26 wherein the narcotic analgesic is fentanyl.
 28. Themethod of claim 26 wherein the narcotic analgesic is buprenorphine. 29.A method of adjusting the therapeutic dosage of drug delivered through apatient's skin, the method comprising: (a) providing a transdermaldelivery system that comprises a plurality of patch units, wherein eachpatch unit comprises a backing layer having one or more borders, a druglayer comprising a drug disposed on the backing layer, and an adhesivelayer, wherein the drug is a narcotic analgesic, a local anesthetic, asedative, a tranquilizer, or a combination thereof, and wherein at leasta portion of the adhesive layer is disposed on the borders of thebacking layer; the patch units are connected to each other along one ormore borders of the patch units; and each patch unit is defined by oneor more lines of separation along the borders of the patch units; (b)separating a first number of patch units from the transdermal deliverysystem along at least one line of separation; (c) applying the firstnumber of patch units such that the drug layer makes contact with theskin; (d) thereafter, separating a second number of patch units from thedelivery system along at least one line of separation, the second numberof patch units being different than or the same as the first number ofpatch units; and (e) applying the second number of patch units such thatthe drug layer makes contact with the skin.
 30. The method of claim 29wherein one or more patch units from the first number of patch units areremoved from the skin before applying the second number of patch unitsto the skin.
 31. The method of claim 29 wherein one or more patch unitsfrom the first number of patch units remain on the skin before applyingthe second number of patch units to the skin.
 32. The method of claim 29wherein the drug is fentanyl, etorphine, buprenorphine, penzocaine,morphine, morphine derivative, lidocaine, prilocaine, mepivacaine,pentabarbital sodium, phenobarbital, secobarbital sodium, codeine,(a-bromoisovaleryl)urea, carbromal, sodium phenobarbital, or acombination thereof.
 33. The method of claim 29, comprising increasingthe dosage of drug through the patient's skin, wherein the second numberof patch units is greater than the first number of patch units.
 34. Themethod of claim 29, comprising decreasing the dosage of drug through thepatient's skin, wherein the second number of patch units is less thanthe first number of patch units.
 35. A method of adjusting thetherapeutic dosage of drug delivered through a patient's skin, themethod comprising: (a) providing a transdermal delivery system thatcomprises a plurality of patch units, wherein each patch unit comprisesa backing layer having one or more borders, a drug layer comprisingfentanyl disposed on the backing layer, and an adhesive layer, whereinat least a portion of the adhesive layer is disposed on the borders ofthe backing layer; the patch units are connected to each other along oneor more borders of the patch units; and each patch unit is defined byone or more lines of separation along the borders of the patch units;(b) separating a first number of patch units from the transdermaldelivery system along at least one line of separation; (c) applying thefirst number of patch units such that the drug layer makes contact withthe skin; (d) thereafter, separating a second number of patch units fromthe delivery system along at least one line of separation, the secondnumber of patch units being different than or the same as the firstnumber of patch units; and (e) applying the second number of patch unitssuch that the drug layer makes contact with the skin.
 36. The method ofclaim 35 wherein one or more patch units from the first number of patchunits are removed from the skin before applying the second number ofpatch units to the skin.
 37. The method of claim 35 wherein one or morepatch units from the first number of patch units remain on the skinbefore applying the second number of patch units to the skin.
 38. Themethod of claim 35, comprising increasing the dosage of fentanyl throughthe patient's skin, wherein the second number of patch units is greaterthan the first number of patch units.
 39. The method of claim 35,comprising decreasing the dosage of fentanyl through the patient's skin,wherein the second number of patch units is less than the first numberof patch units.
 40. A method of adjusting the therapeutic dosage of drugdelivered through a patient's skin, the method comprising: (a) providinga transdermal delivery system that comprises a plurality of patch units,wherein each patch unit comprises a backing layer having one or moreborders, a drug layer comprising buprenorphine disposed on the backinglayer, and an adhesive layer, wherein at least a portion of the adhesivelayer is disposed on the borders of the backing layer; the patch unitsare connected to each other along one or more borders of the patchunits; and each patch unit is defined by one or more lines of separationalong the borders of the patch units; (b) separating a first number ofpatch units from the transdermal delivery system along at least one lineof separation; (c) applying the first number of patch units such thatthe drug layer makes contact with the skin; (d) thereafter, separating asecond number of patch units from the delivery system along at least oneline of separation, the second number of patch units being differentthan or the same as the first number of patch units; and (e) applyingthe second number of patch units such that the drug layer makes contactwith the skin.
 41. The method of claim 40 wherein one or more patchunits from the first number of patch units are removed from the skinbefore applying the second number of patch units to the skin.
 42. Themethod of claim 40 wherein one or more patch units from the first numberof patch units remain on the skin before applying the second number ofpatch units to the skin.
 43. The method of claim 40, comprisingincreasing the dosage of buprenorphine through the patient's skin,wherein the second number of patch units is greater than the firstnumber of patch units.
 44. The method of claim 40, comprising decreasingthe dosage of buprenorphine through the patient's skin, wherein thesecond number of patch units is less than the first number of patchunits.